rs2915959

Variant names:

• chr19-38506969-T-A
• rs2915959
• NM_000540.3:c.8816+17T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000540.3(RYR1):​c.8816+17T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.28 in 1,611,250 control chromosomes in the GnomAD database, including 67,238 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (8622 hom., cov: 31)
  • Exomes 𝑓: 0.28 (58616 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: -3.46
• Publications: 12 publications found

Genes affected

RYR1 (HGNC:10483): (ryanodine receptor 1) This gene encodes a ryanodine receptor found in skeletal muscle. The encoded protein functions as a calcium release channel in the sarcoplasmic reticulum but also serves to connect the sarcoplasmic reticulum and transverse tubule. Mutations in this gene are associated with malignant hyperthermia susceptibility, central core disease, and minicore myopathy with external ophthalmoplegia. Alternatively spliced transcripts encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

RYR1 Gene-Disease associations (from GenCC):

• malignant hyperthermia, susceptibility to, 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, Ambry Genetics
• congenital multicore myopathy with external ophthalmoplegia

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
• RYR1-related myopathy

  Inheritance: AR, AD Classification: DEFINITIVE Submitted by: ClinGen
• central core myopathy

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
• King-Denborough syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• malignant hyperthermia of anesthesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive centronuclear myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• benign Samaritan congenital myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• congenital myopathy with myasthenic-like onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• lethal multiple pterygium syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 19-38506969-T-A is Benign according to our data. Variant chr19-38506969-T-A is described in ClinVar as Benign. ClinVar VariationId is 93303.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.443 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000540.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR1	NM_000540.3	MANE Select	c.8816+17T>A		intron	N/A	NP_000531.2
	RYR1	NM_001042723.2		c.8816+17T>A		intron	N/A	NP_001036188.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR1	ENST00000359596.8	TSL:5 MANE Select	c.8816+17T>A		intron	N/A	ENSP00000352608.2
	RYR1	ENST00000355481.8	TSL:1	c.8816+17T>A		intron	N/A	ENSP00000347667.3
	RYR1	ENST00000594335.6	TSL:1	n.8816+17T>A		intron	N/A	ENSP00000470927.2

Frequencies

GnomAD3 genomes AF: 0.326 AC: 49396 AN: 151504 Hom.: 8586 Cov.: 31

Gnomad AFR AF: 0.431

Gnomad AMI AF: 0.260

Gnomad AMR AF: 0.356

Gnomad ASJ AF: 0.258

Gnomad EAS AF: 0.361

Gnomad SAS AF: 0.458

Gnomad FIN AF: 0.290

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.253

Gnomad OTH AF: 0.336

GnomAD2 exomes AF: 0.320 AC: 80107 AN: 250066 AF XY: 0.320

Gnomad AFR exome AF: 0.437

Gnomad AMR exome AF: 0.391

Gnomad ASJ exome AF: 0.242

Gnomad EAS exome AF: 0.339

Gnomad FIN exome AF: 0.295

Gnomad NFE exome AF: 0.255

Gnomad OTH exome AF: 0.304

GnomAD4 exome AF: 0.275 AC: 402080 AN: 1459630 Hom.: 58616 Cov.: 38 AF XY: 0.280 AC XY: 203207 AN XY: 726104

African (AFR) AF: 0.433 AC: 14469 AN: 33412

American (AMR) AF: 0.387 AC: 17290 AN: 44652

Ashkenazi Jewish (ASJ) AF: 0.252 AC: 6585 AN: 26136

East Asian (EAS) AF: 0.338 AC: 13408 AN: 39678

South Asian (SAS) AF: 0.444 AC: 38233 AN: 86130

European-Finnish (FIN) AF: 0.293 AC: 15599 AN: 53308

Middle Eastern (MID) AF: 0.329 AC: 1408 AN: 4282

European-Non Finnish (NFE) AF: 0.250 AC: 277423 AN: 1111806

Other (OTH) AF: 0.293 AC: 17665 AN: 60226

GnomAD4 genome AF: 0.326 AC: 49493 AN: 151620 Hom.: 8622 Cov.: 31 AF XY: 0.334 AC XY: 24698 AN XY: 74042

African (AFR) AF: 0.432 AC: 17850 AN: 41328

American (AMR) AF: 0.356 AC: 5422 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.258 AC: 891 AN: 3458

East Asian (EAS) AF: 0.360 AC: 1839 AN: 5106

South Asian (SAS) AF: 0.459 AC: 2199 AN: 4794

European-Finnish (FIN) AF: 0.290 AC: 3048 AN: 10494

Middle Eastern (MID) AF: 0.313 AC: 92 AN: 294

European-Non Finnish (NFE) AF: 0.253 AC: 17202 AN: 67906

Other (OTH) AF: 0.341 AC: 713 AN: 2092

Alfa AF: 0.276 Hom.: 1128

Bravo AF: 0.333

Asia WGS AF: 0.484 AC: 1682 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	1	Central core myopathy (1)
-	-	1	Congenital multicore myopathy with external ophthalmoplegia (1)
-	-	1	King Denborough syndrome (1)
-	-	1	not provided (2)
-	-	1	RYR1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.074
DANN	Benign	0.40
PhyloP100		-3.5
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2915959; hg19: chr19-38997609; COSMIC: COSV62099492; COSMIC: COSV62099492;